The serum protease inhibitor alpha 1-antitrypsin (AAT) functions as a phase reactant neutralizer of proteolytic enzymes from tissues during inflammatory processes. It also is part of the regulatory mechanism of the hemostatic and fibrinolytic systems. Individual serum levels and type are genetically determined by a pair of codominant alleles. An association between a deficiency of AAT and hepatocarcinoma has been suggested based on case reports in the literature. We are evaluating the risk of developing hepatocarcinoma in AAT variants, by studying families in which deficiency alleles such as I,S,Z and null are segregating. Families are identified through propositi with neonatal liver disease, chronic pulmonary disease, ciliac disease or serendipitously. Detailed family histories are obtained; hospital records and death certificates are obtained where possible. By Pi typing all living family members, the Pi types of deceased individuals may often be deduced. We are studying a minimum of 100 families. The population under study will be analyzed for an increase in hepatocarcinoma in proven or probable carriers of Pi deficiency genes. Pi normal (MM) individuals in the same families, siblings and mates will serve as a double set of controls. The groups will be compared to U.S. mortality statistics. We will also analyze the data for frequency of any other neoplasm, whose occurrence warrents it. In addition to defining the frequency of hepatocarcinomia in this population we will look for other factors which may influence the development of malignancy in Pi deficient individuals.